Background NKX019 is an investigational CD19-targeting chimeric antigen receptor (CAR) natural killer (NK) cell therapy with engineered persistence for treating B cell malignancies. NKX019 exhibits more rapid cytotoxic kinetics than CD19-directed CAR T cells, and lower production of cytokines associated with cytokine release syndrome (CRS).1 The safety and clinical activity of NKX019 are currently being evaluated in a phase I [GM1] clinical study [NCT05020678]. Recent studies2,3 have shown that combining NK cell therapies with monoclonal antibodies (mAbs) may improve targeted NK cell activation and overcome some of the disadvantages associated with the stand-alone use of therapeutic mAbs. CD20-targeted mAbs such as rituximab (RTX) and obinutuzumab (OBI), can mediate antibody-dependent cellular cytotoxicity (ADCC), a key effector mechanism of NK cells. RTX also activates some levels of caspase-dependent direct cell death (DCD). OBI is engineered to induce improved DCD and ADCC mechanisms.4 Antigen escape is reported in 30–95% of relapses after CD19-directed CAR T cell therapy in B cell –acute lymphoblastic leukemia (B-ALL).5 Here, we describe the potential advantage of using NKX019 in combination with [GM2] RTX or OBI to reduce relapse following monotherapy with either agent alone by targeting both CD19+and CD20+ malignant B cells.
Methods NK cells, isolated from healthy PBMCs, were expanded and engineered to express a CD19-targeted CAR and membrane-bound interleukin 15 to generate NKX019. NKX019 cells were cryopreserved and freshly thawed for experimental use.NKX019 mediated-cytotoxicity was assessed in both 4-Hour (4H) and extended assays in the presence or absence of anti-CD20 mAbs, RTX or OBI, using CD19+ and CD20+ expressing tumor B cell lines: Raji (lymphoblast-like), DOHH-2 (follicular lymphoma) and EHEB (B-Lymphoblastoid) cells. A non-glycosylated version of RTX (RTX mutant) with compromised ADCC function was used to evaluate ADCC-mediated vs ADCC-independent activity of NKX019.
Results NKX019 in combination with RTX or OBI demonstrated increased activity and persistence against tumor B cell lines in a 4H kill assay and in tumor rechallenge experiments. NKX019 in combination with RTX demonstrated an enhanced cytotoxicity against EHEB lymphoblastoid cell line in a manner consistent with ADCC. OBI demonstrated increased activity in comparison to RTX, as a single agent and in combination with NKX019 cells.
Conclusions This study demonstrates increased activity and persistence of NKX019 when used in combination with approved CD20-targeted mAbs, RTX and OBI, against B cell malignancies. A first-in -human Phase I clinical trial of NKX019 in combination with RTX is planned.
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Cichocki F, Bjordahl R, Gaidarova S, et al. iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy. Sci Transl Med. 2020;12(568):eaaz5618.
Luo C, Wu G, Huang X, et al. Efficacy and safety of new anti-CD20 monoclonal antibodies versus rituximab for induction therapy of CD20+B-cell non-Hodgkin lymphomas: a systematic review and meta-analysis. Sci Rep. 2021;11(1):3255.
Spiegel JY, Patel S, Muffly L, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021;27(8):1419–1431.
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